Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers
Transport of a novel anti-cancer agent, fenretinide across Caco-2 monolayers
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DOI：
10.1007/s10637-006-9026-3
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发表时间：
2007-06-01
影响因子：
3.4
通讯作者：
Jasti, Bhaskara
中科院分区：
文献类型：
--
作者：
Kokate, Amit;Li, Xiaoling;Jasti, Bhaskara
芬维A胺是一种合成的类维生素A，具有针对多种恶性肿瘤的化疗活性。动物口服给药后，发现芬维A胺不完全吸收，主要通过粪便排出。本研究的目的是利用 Caco-2 单层细胞确定芬维A胺口服吸收不良的可能原因。为了实现这一目的，使用了芬维A胺与聚维酮K25的固体分散体。在接受者中存在牛血清白蛋白 (BSA) 的情况下，测定了芬维A胺跨 Caco-2 单层的表观渗透系数 (P-app)。进行顶端到基底外侧（AP-BL）和基底外侧到顶端（BL-AP）通量研究以确定外排机制的作用。在接收器中存在 4% BSA 的情况下，发现 P-app 为 (8.8 +/- 0.5) x 10(-8) cm/sec。在接收器中存在 4% BSA 的情况下，AP-BL 通量随着芬维A胺浓度 (125-640 μM) 的增加而线性增加。外排和细胞旁途径对芬维A胺的渗透性影响不显着。大量的药物，大约是初始量的13-15%积聚在细胞膜中。 3 小时内，供体中芬维A胺的量减少了 16%。然而，在接收器中只发现了初始数量的 0.12%。此外，P-app 随着接受者血浆蛋白浓度的增加而增加。根据这些结果，芬维A胺的较差渗透性可归因于其在亲脂性细胞膜中的积累以及在接受介质中的分配较差。
Fenretinide is a synthetic retinoid with chemotherapeutic activity against various malignancies. Upon oral administration to animals, fenretinide was found to be incompletely absorbed and excreted primarily in feces. The purpose of this study was to determine the possible reasons for poor oral absorption of fenretinide using Caco-2 cell monolayers. To achieve this purpose, a solid dispersion of fenretinide with Povidone K25 was used. The apparent permeability coefficient (P-app) of fenretinide across Caco-2 monolayers in the presence of bovine serum albumin (BSA) in the receiver was determined. Apical to basolateral (AP-BL) and basolateral to apical (BL-AP) flux studies were performed to determine the role of an efflux mechanism. In the presence of 4% BSA in the receiver, the P-app was found to be (8.8 +/- 0.5) x 10(-8) cm/sec. The AP-BL flux increased linearly with an increase in fenretinide concentration (125-640 mu M) in the presence of 4% BSA in the receiver. Efflux and paracellular pathways played an insignificant role in the permeability of fenretinide. A significant amount of drug, approximately 13-15% of the initial amount accumulated in the cell membrane. The amount of fenretinide in the donor decreased by 16% over a 3 h period. However, only 0.12% of the initial amount was found in the receiver. Also, the P-app increased with an increase in plasma protein concentration in the receiver. On the basis of these results, the poor permeability of fenretinide can be attributed to its accumulation in the lipophilic cell membrane and poor partitioning into the receiver medium.